SUN-290 The c-MET Inhibitor Tepotinib Elicits Growth Inhibitory Activity on Pancreatic Neuroendocrine Tumors Associated with MEN1

Abstract Disclosure: P. Bolel: None. L.S. Weinstein: None. S.K. Agarwal: None. Patients with Multiple Endocrine Neoplasia Type 1 (MEN1) are predisposed to develop various endocrine and non-endocrine tumors during their lifetime due to germline mutations in the MEN1 tumor suppressor gene that encodes menin. Pancreatic neuroendocrine tumors (PNETs) are a main cause of premature mortality in MEN1 patients due to disease progression after surgery or current chemotherapy options. PNETs also develop in mouse models of germline heterozygous or pancreatic islet β-cell specific Men1 loss serving as valuable surrogates for testing potential therapeutic strategies. Overexpression and activation of the oncogenic tyrosine kinase receptor c-MET has been observed in human and mouse PNETs, and c-MET activation was essential for the growth of PNETs in mouse xenografts. Cabozantinib, an inhibitor of multiple tyrosine kinases (including c-MET) significantly extended the progression-free survival of patients with advanced PNETs in the recent Phase-3 CABINET trial. Tepotinib is a highly selective, orally bioavailable small-molecule MET inhibitor (METi) that inhibits phosphorylation at c-MET residues Y1234/1235 leading to the inactivation of downstream signaling pathways. Therefore, we have tested the possibility of specifically targeting c-MET with Tepotinib in PNETs that develop in the mouse model of β-cell specific Men1 loss (RIP-Cre;Men1f/f). Primary tumor cells were isolated from the PNETs of RIP-Cre;Men1f/f mice and treated with various concentrations of Tepotinib in-vitro, followed by RealTime-Glo assay at various time points post-treatment to measure cell viability and insulin assay to assess β-cell function. Bulk RNA-seq was performed to determine gene expression changes in Tepotinib treated vs. DMSO-treated cells. At the 24h time-point, 5µM Tepotinib caused more than 50% reduction in cell viability and a significant reduction in the amount of insulin secreted in the cell culture medium. Analysis of bulk RNA-seq data showed that Tepotinib treatment decreased the level of transcripts associated with cell cycle progression suggesting that a combination therapy with cell cycle inhibitors may enhance Tepotinib efficacy in PNET cells. Further preclinical and clinical evaluation will be important to consider Tepotinib as a treatment option for PNETs. Presentation: Sunday, July 13, 2025